EXPERIMENTAL AND THERAPEUTIC MEDICINE 20: 117-120, 2020

Botulinum toxin in low urinary tract disorders

‑ over 30 years of practice (Review)
ARSENIE DAN SPINU1,2, OVIDIU GABRIEL BRATU1‑3, CAMELIA CRISTINA DIACONU1,4,
ANA MARIA ALEXANDRA STANESCU1, SIMONA BUNGAU5, OVIDIU FRATILA6,
ROXANA BOHILTEA1,7 and DAN LIVIU DOREL MISCHIANU1‑3

1
‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest;
2
Urology Department, Emergency University Central Military Hospital, 010825 Bucharest;
3
Academy of Romanian Scientists, 050045 Bucharest;
4
Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 014461 Bucharest;
5
Department of Pharmacy, University of Oradea, Faculty of Medicine and Pharmacy, 410028 Oradea;
6
Department of Medical Disciplines, University of Oradea, Faculty of Medicine and Pharmacy, 410087 Oradea;
7
Department of Obstetrics and Gynecology, University Emergency Hospital, 050098 Bucharest, Romania

Received February 3, 2020; Accepted March 3, 2020

DOI: 10.3892/etm.2020.8664

Abstract. Botulinum toxin is a substance produced by Contents

Clostridium Botulinum and is responsible for human botulism.
This substance is a poison, a neurotoxin, but used in limited
quantities it can be a cure for some diseases. It is well connected
to a large variety of medical applications. The mechanism of
action relies on blocking the acetylcholine at the neuromus-
cular junction, which blocks the transmission of the nervous
impulse with secondary flaccid paralysis. In urology, its role
in idiopathic overactive bladder and neurogenic bladder is
well known. We performed a thorough review using PubMed
and other databases, revising the mechanisms of botulinum
toxin action in urologic pathology, treatment procedures and
other options. Botulinum toxin is a well‑studied substance
with a large number of applications in medicine. In urologic
pathology, overactive bladder and neurogenic bladder are
backed by robust studies that support the therapeutic role of
this substance. The toxin has multiple effects, such as inhibi-
tion of the nerve growth factor, blocking the bladder sensory
afferent pathway and apoptotic effect on the prostate tissue, by
inhibiting the substance P, altering the nociceptive pathways.
Interstitial cystitis and other rare pathologies show promising
results, but further studies are needed. The role of botulinum
toxin in benign prostatic hyperplasia is still not elucidated.
Correspondence to: Professor Ovidiu Gabriel Bratu, ‘Carol Davila’
University of Medicine and Pharmacy, 37 Dionisie Lupu Street,
020021 Bucharest, Romania
E‑mail: ovi78doc@yahoo.com
Key words: botulinum toxin, overactive bladder, neurologic
bladder, treatment, analysis
1. Introduction
2. Materials and methods
3. Results
4. The mechanism of action
5. Studies of efficiency
6. Conclusions
1. Introduction
The first medical use of botulinum toxin dates back to 1988,
when Dykstra et al used it in detrusor external sphincter
dyssynergia (1). Since then, this poison began to be widely
used in medical practice for chronic migraines, chronic pain,
head and neck dystonias, strabismus, hyperhidrosis and anal
fissures (2). Botulinum toxin is a poison, a neurotoxin, but
used in limited quantities it can be a cure for some diseases.
The first medical use of this neurotoxin dates back to 1981,
when Scott used it to correct strabismus (3). American
Urological Association (AUA) recommends this type of
treatment for refractory overactive bladder. Federal Drug
Administration (FDA) officially approved the usage of botu-
linum toxin in August 2011.
As of general recommendations, botulinum toxin is the
third line of treatment option for overactive bladder. Although
it has clear benefits, there are also side effects that can not
be ignored including urinary tract infections and elevated
post‑void residual volume.
There are eight different strains of toxin: A, B, C1, C2,
D, E, F and G. The most widely used in medicine is the
A subtype. This strain has much longer lasting effects than
all the others, which is a great advantage given the fact that
the instillation is an invasive procedure. The B subtype is also
used, but it has a shorter duration of action and there are not
many studies on it.
118 SPINU et al: BOTULINUM TOXIN IN LOW URINARY TRACT DISORDERS
2. Materials and methods
PubMed and Scopus databases were searched for reviews and
original articles regarding Botulinum toxin overactive bladder
and neurogenic bladder. Morphopathology and the clinical use
were envisaged. Side effects were taken to consideration.
3. Results
Botulinum toxin has many medical uses. Its effect on overac-
tive bladder and neurogenic bladder were searched. These two
pathologies have many common characteristics, but also some
differences. Overactive bladder, so‑called idiopathic bladder,
reunites all the causes that can not be included in the neurogenic
bladder category, so it is an exclusion diagnosis. Overactive
bladder (OAB) is defined by the International Continence
Society as urgency with or without urinary incontinence (UI),
usually associated with frequency and nocturia. It is a multifac-
torial and common disease, associated with detrimental effects
on the quality of life and a great economic burden. Neurogenic
detrusor overactivity (NDO) is defined as a special type of
OAB, when there is a relevant underlying neurological condi-
tion, such as spinal cord injury or multiple sclerosis (4‑6).
4. The mechanism of action
Botulinum toxin is one of the most potent neurotoxins. It has
been calculated that 1 g of this purified substance can kill over
1 million people (7). It is a 150 kDa polypeptide with three
separate domains: N, middle and C. The C domain binds to
the pre‑synaptic membrane, the N domain is a specific poly-
peptidase and the middle domain facilitates the L chain into
the cytosol. The most remarkable aspect is the affinity of this
substance for the most active synapses.
The mechanism of action relies on blocking the acetylcholine
at the neuromuscular junction, which blocks the transmission of
the nervous impulse with secondary flaccid paralysis.
The toxin has multiple effects such as inhibition of the nerve
growth factor, it blocks the bladder sensory afferent pathway,
it has apoptotic effect on the prostate tissue, by inhibiting the
substance P, altering the nociceptive pathways (8‑10). This
type of paralysis lasts from 3 to 6 months when injected into
the neuromuscular junction of the skeletal muscle and more
than one year if the injection is made into the smooth muscle.
There are many commercially available products, starting
with Botox (onabotulintoxin), Dysport (abobotulintoxin) and
Xeomin (incobotulintoxin). There is no direct equivalency
between doses, but it is generally accepted that one unit of
onabotulinum is equivalent to 3‑5 units of abobotulinum.
There is still no equivalency with incobotulintoxin (11‑13).
Its usage is accepted for overactive bladder, in fact both
European and American guidelines recommend this type of
treatment as a third line therapy. There are numerous studies
that compare the effectiveness of botulinum toxin against oral
therapies.
5. Studies of efficiency
One of the most comprehensive meta‑analysis was carried out
by Drake et al (14). In the study, 56 randomized controlled
trials were revised comparing onabotulinum toxin to oral
medication, including mirabegron and anticholinergics. They
used network meta‑analysis and network meta regression for
comparison and adjusted the baseline for severity symptoms.
The set period was 12 weeks, the span of the review ranged
from 2007 to 2014 and only studies in English were eligible.
All medications had higher efficiency than placebo, with
onabotulinumtoxin being superior to oral medication in every
aspect of micturition, urgency, urinary incontinence episodes.
Regarding side effects, onabotulinumtoxin led to urinary tract
infection, urinary retention, bacteriuria, increased residual
urine volume and haematuria. Onabotulinumtoxin had also
the best results in relieving the oaveractive bladder symptoms.
One suggestive example of the superiority of this toxin
over oral medication was presented by Ferreira et al (15). Their
small study included 61 patients who were randomly selected
to oral or toxin medication. Of the patients 23.5% with oral
medication and 11.8% from the onabotulinum group were
non‑responders. Macroscopic haematuria was present in 28%
of the onabotulinum patients and dry mouth in 72% of the
patients with oral medication. The study reported the superi-
ority of onabotulinum toxin to oral medication in almost all
aspects of urodinamics, continence and quality of life. Most
important, all patients were from the neurogenic bladder group,
not from the overactive bladder group. Schurch et al (16) also
reported an improvement in quality of life. Karsenty et al (17)
reported urinary continence in 40‑80% of the cases.
There are other studies that compared the toxin to placebo.
One of the most recent reviews is by Zhou et al (18). Using many
databases, they searched for the efficacy and safety of botulinum
toxin in the treatment of neurogenic bladder. They identified four
articles including 932 patients, from whom 450 were included in
the botulinum group and 482 in the control group. The authors
found that onabotulinum toxin is very efficient in comparison to
placebo, regardless of the dosage. Also, treatment complications
are mostly related to urinary tract and include urinary infection,
urinary retention, and haematuria (19).
One of the most important issues of overactive and neuro-
logic bladder is the high pressure inside the bladder during
voiding. There are many discussions regarding the need of
urodynamics in patients following treatment for overactive
or neurologic bladder. Koschorke et al (20) evaluated the
need for urodynamics in patients with neurologic overactive
bladder under treatment with onabotulinum toxin. Their study
group included 148 patients who were evaluated before and
6 weeks after receiving the treatment. High intravesical pres-
sure leads to renal failure later, so it is mandatory to evaluate
the patient carefully. The authors determined a pressure higher
than 40 mmH 2O before receiving the treatment indicates
a poor prognosis for urodynamic outcomes. Even if 66% of
the patients became continent, one out of five had high intra-
vesical pressure, putting the upper urinary tract at risk. After
repeating the treatment, 10 out of 18 patients achieved normal
vesical pressure. There were still 8 patients out of 148 who did
not achieve a normal intravesical pressure status. Thus, these
authors underlined the need for urodynamics (20).
Another debated problem was the dosage of the substance.
Every pharmaceutical company that produces some form of
the toxin has its own measure, there is no a standardized one.
Moreover, there is still debate on what quantity of the same
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 20: 117-120, 2020
toxin has greater efficiency. Zhang et al (21), tried to eluci-
date this subject. Participants (1,879) from eight studies were
included in their analysis. Besides the good efficiency of the
drug, the authors emphasize the differences that appear with
varying doses. Their comparison between 200 and 300 units
did not find any significant differences, but the Cochrane
review has some interesting findings: lower doses of the drug
appear to have beneficial effects, but higher doses have better
efficiency (and also a higher rate of side effects), suburothelial
injection seems to have the same effect as intradetrusor injec-
tion, and the effect is dose and toxin type‑dependant (22).
Many authors considered that single dose treatment is
the optimal medical approach, but there are studies that have
found that repeat treatment can be used in the same patient.
Denys et al (23) proved that patients with neurogenic bladder
can be treated with repeated injections of botulinum toxin.
Moreover, even patients who do not achieve a good perfor-
mance status after the first dose can respond better after
repeated treatment. Other studies also concluded that there is
no refractory response with repeated treatment.
The first study that investigated this toxin in the treatment
of neurogenic bladder dates back to 2005. Schurch et al (24)
evaluated 59 patients with neurogenic bladder who received a
single dose of toxin (200 or 300 units) or placebo. The results
were spectacular, a significant improvement in all aspects was
observed.
Another aspect is the place of injection. As yet, there is
no standardized recommendation for injection site. There are
studies that compared trigone versus outside the trigone and
concluded that trigonal injection is superior (25,26).
The side effects of this substance in pregnancy are less
studied. FDA put botulinum toxin in category C for pregnant
women, indicating a major teratogen. Moreover, great care
must be taken in elderly patients or those aged under 18 years.
The follow up is another debated problem. There are no
guidelines regarding the follow-up of these patients, but given
the fact that these diseases are progressive, the patients should
be monitored.
There are studies that tried to link this medication to other
neurological disorders such as Parkinson's disease, multiple
sclerosis, spinal cord injury, cerebrovascular accident and
myelomeningocele. Some of the results were promising, but
there are no standardized recommendations.
Cheng et al (27), in their review, evaluated the efficacy and
safety of the toxin in the treatment of neurogenic bladder. In
the same study, they evaluated the differences regarding the
dosage. They found out that there are no differences between
200 and 300  units. Patients (1,915) from six studies were
included in their review, with great improvements in the toxin
group regarding urinary incontinence, maximum detrusor
pressure and maximum cystometric capacity.
Some authors have tried to expand the use of this medica-
tion. Trinh et al (28) evaluated the efficacy of botulinum toxin
in a small group of patients with failed sacral modulation. The
results were encouraging, but far inferior to the patients with
no sacral modulation treatment.
New applications of this medication include benign pros-
tate hyperplasia and chronic prostatitis, with contradictory
results (29,30). Jhang and Kuo (31), in their study, reviewed all
current applications of this medication.
119
There are studies that evaluated botulinum toxin injections
in patients with severe comorbidities (32,33). Liao et al (34)
concluded that it is safe, but caution should be taken. Post
voiding residue is a very important complication that needs
to be monitored and also the success of this procedure is rela-
tively lower in frail patients.
6. Conclusions
Evidence for the use of botulinum toxin in overactive bladder and
neurogenic bladder continues to accumulate. This type of treat-
ment offers a reasonable alternative to neural stimulation. It has
limited side effects, generally related to the surgical procedure.
One severe possible complication is the post voiding
residue. The elderly and neurological patient should be treated
carefully. Another complication is the high intravesical pres-
sure, which may lead in time to renal failure. Urodynamics in
this type of patients is mandatory, pre- and post‑injecting the
medication. Patients with multiple sclerosis have increased risk
of urinary infections, so particular attention is recommended.
Novel applications of botulinum toxin may be benign
prostatic hyperplasia, interstitial cystitis, and chronic pelvic
pain, but there are no standardised approaches. There is still
no consensus regarding the injection pattern or a regular dose.
Repeated treatment seems to offer good results in selected
cases. One possible application of this treatment could be for
patients who have undergone augmentation cystoplasty for
the same disease. Also, there is no standardised follow-up
for this type of patients, and no guidelines. There are still
many questions and many fields in which botulinum toxin
can be used. For some diseases, such as overactive bladder
and neurologic bladder, the indications are clear, and these
indications may be expanded to other urologic diseases in
the future.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
AMAS, SB, OF and RB collected, analyzed and interpreted
the patient data regarding the metabolic and cardiovascular
benefits of GLP‑1 agonists. ADS, DLDM, OGB and CCD
substantially contributed to the conception of the work and
interpretation of data; also, they drafted the manuscript and
were major contributors in writing the manuscript. All authors
read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
120 SPINU et al: BOTULINUM TOXIN IN LOW URINARY TRACT DISORDERS
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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